Project summary Ischemic heart disease (IHD) is a major cause of morbidity and mortality in the US. Adult heart is largely dormant, designed primarily to perform pump function and responding to pathological challenge by limited myocyte turnover with development of scar tissue at the site of injury. Incredibly, cardiac tissue during developmental stages consists of actively diving cardiomyocytes and is able to resolve injury by formation of new tissue. The fundamental question is whether adult heart can be somehow driven into a developmental signaling state restoring cellular replacement without compromising pump function. Cardiac progenitor cell- based (CPC) applications have been widely used to resurrect myocardial repair processes and have moved into clinic but are limited due to underperformance of the donated cells. In most cases, CPCs are harvested from elderly patients with an adverse cardiac tissue morphology including host of clinical features reducing therapeutic efficacy of the cells and their cell-free agents such as exosomes. Interestingly, CPCs are known to possess incredible growth and repair properties during fetal and neonatal cardiac stages and understanding unique signaling hubs regulating CPC performance during development may open up a novel avenue for enhancement of CPC therapy. Ideally changing cardiac microenvironment to resemble a developmental cardiac tissue may offer a powerful way to restore lost cardiac repair ability. Our preliminary data indicates miR-294 signaling axis enhances cardiac performance including core CPC function mediated by its downstream target Lin28a. Therefore, we hypothesize that reintroduction of developmental miR-294-Lin28a signaling axis in CPCs will promote CPC properties reminiscent of more primitive developmental stage where the heart can better repair itself. Our goal is to enhance CPC therapy including the potency of cell-free agents such as exosomes by induction of developmental signaling to repair the heart after myocardial damage. We will extend these studies to develop a therapeutic strategy on miR294-Lin28a based modification of human heart derived CPCs and their exosomes that enhances cardiac structure and function after injury. Enhancement of cardiac cell therapy by reintroduction of developmental signaling provides a new direction for CPC based cell therapeutics and treatment of heart failure.